Preparation of biphosphonic acids and salts thereof

ABSTRACT

A process for preparing alendronate sodium includes the reaction of gammabutyric acid with phosphorous acid and phosphorus trichioride and subsequent treatment with an aqueous solution of an alkali metal hydroxide, in which the reaction is conducted in liquid ionic solvents.

CROSS REFERENCE TO RELATED APPLICATIONS

Applicants claim priority under 35 U.S.C. §119 of Italian ApplicationNo. MI2002A000908 filed Apr. 29, 2002. Applicants also claim priorityunder 35 U.S.C. §365 of PCT/IB02/04941 filed Nov. 25, 2002. Theinternational application under PCT article 21 (2) was published inEnglish.

FIELD OF THE INVENTION

The present invention relates to a process for preparing bisphosphonicacids and their pharmacologically active salts.

STATE OF THE ART

The bisphosphonic acids and their salts, which form the subject of thepresent patent application are compounds described by the followingstructural formula:

in which M₁, M₂, M₃, M₄ are selected from H, and a monovalent cation.Belonging to this class of molecules are the following compounds used inthe treatment of osteoporosis (see Table 1) according to the differentmeaning that R₁ may assume.

TABLE 1 R₁ = CH3, Etidronic acid

Zoledronic acid

Risedronic acid

Minodronic acid

Pamidronic acid

Alendronic acid

Neridronic acid

Olpadronic acid

Ibandronic acid

As regards the methods of synthesis, these compounds are synthesizedstarting from the corresponding carboxylic acid according to thesynthetic scheme appearing in Diagram 1

Starting from the acid, by subsequent salification of the acid protons,the various salts may be obtained.

A problem that is commonly encountered in the preparation of thesecompounds is the formation, during the reaction, of very denseunstirrable masses, which render the industrial synthesis of thesesubstances problematical.

In the literature various documents have been published which describetechniques of synthesis of the compounds listed in Table 1.

U.S. Pat. No. 4,621,077, which regards alendronic acid and neridronicacid, describes the use of chlorobenzene as the solvent in thesynthesis. The application of this technique leads to obtaining solidand unstirrable masses in the course of the reaction. A series of otherpatents (U.S. Pat. No. 4,407,761, U.S. Pat. No. 4,327,039, U.S. Pat. No.4,304,734, U.S. Pat. No. 4,267,108, U.S. Pat. No. 4,054,598) envisagesthe use of chlorobenzene as reaction solvent, but also in these casesthe drawback described above is again met with.

U.S. Pat. No. 4,922,007, U.S. Pat. No. 5,019,651 and U.S. Pat. No.5,510,517, as well as J. Org. Chem. 60, 8310, (1995), envisage the useof methanesulphonic acid as reaction solvent. This makes it possible toobtain stirrable masses in the course of the reaction. However, thistechnique, as reported in J. Org. Chem. 60, 8310, (1995), involves risksof safety in that this solvent gives rise to uncontrollable reactions inthe reaction conditions, when the temperature of the reacting mixturesexceeds 85° C. WO9834940 employs polyalkylene glycols as reactionsolvents for synthesizing alendronic acid; however, these solvents havea high cost and are difficult to eliminate from the finished product,given their high boiling point

In WO0049026, starting from a nitrogen-protected derivative ofβ-aminopropionic acid to prevent the known problems of stirrability ofthe reaction mixture, use is made of orthophosphoric acid as thereaction means. The derivatization of the starting product in any caserenders the method of synthesis unwieldy and involves the need forintroducing additional steps for protection and deprotection.

U.S. Pat. No. 5,792,885 synthesizes pamidronic acid starting from anitrogen-protected derivative of γ-aminobutyric acid, in aromatichydrocarbons as the reaction solvents. This method presents the samedrawbacks illustrated for the method described in WO0049026.

WO0110874 regards the use of methanesulphonic anhydride as the solventfor producing alendronic acid, but the high cost of the solvent rendersthe method difficult to apply at an industrial level.

TECHNICAL PROBLEM

The need was thus felt to have available a general process for preparingthe compounds described in Table 1 which would not present the drawbacksof the processes known to the art.

SUMMARY OF THE INVENTION

The present applicant has now unexpectedly found that, using as thereaction solvents in the synthesis of the compounds described in Diagram1 the so-called ionic liquids, it is possible to convert the rawmaterials into the desired products, avoiding the drawbacks of theprocesses known to the prior art.

In addition, the solvent used is economically advantageous and easy torecover and recycle.

Consequently, forming the subject of the present invention are processesfor preparing the active principles described in Table 1, comprising thereaction of the appropriate raw materials with phosphorous acid andphosphorus trichloride, subsequent treatment with acid water andpossible final treatment with an aqueous solution of a hydroxide of analkaline metal, characterized in that the reaction is conducted in ionicliquids at a temperature of between 15° C. and 120° C.

DETAILED DESCRIPTION OF THE INVENTION

M₁-M₄ are preferably selected from the cations of the alkaline metals,H, cations of aliphatic or cyclolaliphatic amines, and more preferablyare sodium and/or H.

The temperature at which the aforesaid ionic solvents are liquid ispreferably between 20° C. and 100° C. By liquid ionic solvents are meantthe -onium salts selected from the group consisting of ammonium,sulphonium or phosphonium salts.

Possible examples of said solvents are given below:

in which each R may be independently H, a linear or branched C₁-C₂₀alkyl group, a cycloalkyl containing from 5 to 6 carbon atoms, alkylenearyl, or aryl; R₂ is H or a linear or branched C₁-C₁₈ alkyl group, X⁻ isan anion selected from the group consisting of halogenide, BF₄ ⁻, PF₆ ⁻,or AlCl₄ ⁻. Particularly preferred is tributylammonium chloride, whichmelts at approximately 60° C.

These solvents are moreover easy to prepare with methods of aconventional type, do not create problems of safety in so far as they donot cause uncontrollable reactions, and moreover afford the undoubtedadvantages that they may be recovered and re-used for several productioncycles.

The following examples are provided by way of non-limiting illustrationsof the process that forms the subject of the present invention.

EXAMPLE 1A

Formation of the Reaction Solvent (Tributylammonium Chloride)

A 3-litre reactor provided with a Dean-Stark trap and drip funnel ischarged with 150 ml of toluene and 334.3 g of tributylamine. Thesolution is cooled to 25-30° C. and from the drip funnel there are added152.6 ml of 33% aqueous hydrochloric acid, in the meantime controllingthat the temperature does not exceed 40° C. The homogeneous solutionthus obtained is then distilled in vacuum conditions (50 mmHg) until theinternal temperature reaches 80° C. and no more liquid is distilled fromthe reactor. The mixture thus obtained consists of tributylammoniumchloride and is ready for use in the subsequent reactions of formationof bisphosphonic acids.

EXAMPLE 1B

Preparation of Sodium Alendronate

To the liquid phase obtained in Example 1, kept at 70° C., there areadded 79.5 g of phosphorous acid and subsequently 100 g ofγ-aminobutyric acid. The temperature of the mixture is brought to 60°C., and from the drip funnel there are added 266.4 g of phosphorustrichloride during an interval of approximately one hour, maintainingthe internal temperature between 60° C. and 65° C. Subsequently, thereaction mixture is kept under stirring for two hours at 60° C., andthen is cooled to 20° C. There are added 410 ml of deionized water,keeping the temperature of the reaction mixture below 40° C. At the endof addition, the temperature is brought up to 90° C. and kept in theseconditions for 2 hours. After cooling to 10° C., 1093 ml of 30% aqueoussodium hydroxide are added to the reaction mixture, until the final pHis 11-12. The resulting top layer, consisting of tributylamine isseparated off. The tributylamine may be subsequently treated withaqueous hydrochloric acid, as described in Example 1A, to re-obtaintributylammonium hydrochlorate as the reaction solvent.

The aqueous phase is treated with 33% aqueous hydrochloric acid to bringthe pH of the solution to 4.3±0.1. The aqueous phase is then dripped on7000 ml of methanol under stirring, causing the separation of a heavyprecipitate, which is then filtered and washed with 500 ml of methanol.

There are obtained 1366 g of crude sodium alendronate, which is thendissolved at 75° C. in 3600 ml of deionized water. The solution is thenfiltered at 75° C. and left to crystallize by means of slow cooling,until the mixture reaches 5° C. The crystalline solid obtained isfiltered and washed with 2×100 ml of deionized water and then dried at50° C. for 12 hours, to obtain 97.8 g of sodium alendronate (31% yield).

EXAMPLE 2

Preparation of Zoledronic Acid

20 of tributylammonium chloride, prepared as in Example 1A, are put intoa 100-ml flask provided with coolant, magnetic stirrer, drip funnel andthermometer. The solid is melted at 60° C., then 3.2 g of phosphorousacid and 5.0 g of 2-(1-imidazyl)-acetic acid are added. The temperatureof the mixture is then brought up to 65-70° C., and from the drip funnelthere are slowly added 10.9 g of PCl₃. Once the addition is completed,the mixture is brought up to 80° C. and kept under these conditions fortwo hours, at the end of which 20 ml of deionized water are added. Themixture is brought to 90° C. and is kept under these conditions for 2hours. It is then cooled down to room temperature, and 50 ml of 33% NaOHare added to the mixture, until a pH of the mixture ≧12 is reached. Thetwo phases that have formed are separated, and 20 ml of toluene areadded to the aqueous bottom phase, stirring the mixture for 15 min. Thephases are once more separated, and the aqueous phase is brought to pH 1by addition of 33% HCl. The aqueous solution is then dripped on 300 mlof methanol. The solid that precipitates is filtered and washed with 50ml of methanol.

To the filtered solid there are added 70 ml of deionized water, and themixture is heated to 80° C. and kept under these conditions for 1 hour.Then the solution is cooled to room temperature. A white solidprecipitates, which is filtered and washed with 20 ml of deionized waterto obtain 4.2 g of the desired product, which is dried at 50° C. undervacuum for 6 hours. The weight of the dry product is 2.8 g.

EXAMPLE 3

Preparation of Risedronic Acid

The same procedure of preparation as the one described in Example 3 isfollowed, using 5.4 g of 2.-(3-pyridyl)-acetic acid instead of2-(1-imidazyl)-acetic acid; 3.5 g of the desired product are obtained.

EXAMPLE 4

Preparation of Sodium Pamidronate

The same procedure of preparation as the one described in Example 1 isfollowed, using 86.4 g of β-aminopropionic acid instead ofγ-aminobutyric acid; 81.5 g of the desired product are obtained.

1. A process for preparing bisphosphonic acids and their salts offormula

in which R₁ has the meanings indicated in the following Table 1: R₁ =CH3, Etidronic acid

Zoledronic acid

Risedronic acid

Minodronic acid

Pamidronic acid

Alendronic acid

Neridronic acid

Olpadronic acid

Ibandronic acid

and in which M₁, M₂, M₃, M₄ are selected from H, and a monovalentcation, comprising the reaction of acids of formula R₁-CO₂H, in which R₁has the aforesaid meanings, with acids and phosphorus trichloride,wherein the reaction is conducted in ionic liquids as the reactionsolvents, at a temperature of between 15° C. and 120° C. wherein saidionic liquids are selected from the group consisting of salts ofammonium, sulphonium or phosphonium having the following formulas

in which each R may be independently a linear or branched C₁—C₂₀ alkylgroup, a cycloalkyl containing from 5 to 6 carbon atoms, alkylene aryl,or aryl; R₂ is H or a linear or branched C₁—C₁₈ alkyl group, X⁻ is ananion selected the group consisting of halogenide, BF₄ ⁻, PF₆ ⁻, andAlCl₄ ⁻.
 2. The process according to claim 1, wherein the temperature atwhich the aforesaid ionic solvents are liquids is between 20° C. and100° C.
 3. The process according to claim 1, wherein M₁−M₄ are selectedfrom the cations of an alkaline metal, H or the cations of aliphatic orcycloaliphatic amines.
 4. The process according to claim 3, whereinM₁-M₄ are selected from H and/or sodium.